tbuckley/cabot-search huggingface dataset:
Adolescents and youth are prioritising human rights in the climate change agenda
Authors: Giulia Gasparri, David Imbago-Jácome, Heeta Lakhani, William Yeung, Omnia El Omrani
Journal: BMJ (2022)

<h3>Background</h3> The literature has not distinguished between LF “hypertrophy” and “buckling” when addressing cervical spondylotic myelopathy. The identification of buckling on dynamic magnetic resonance imaging can determine the levels for decompression more accurately and modify the surgical plan accordingly. No studies have been performed in the cervical spine to analyze the factors affecting LF buckling. <h3>Purpose</h3> Our objective was to investigate the factors affecting static ligamentum flavum (LF) “hypertrophy” and dynamic LF “buckling.” <h3>Study Design</h3> Retrospective cohort study. <h3>Methods</h3> We conducted a retrospective study of hospital records and imaging database from January 2014 to January 2020. The relation of age, disc height, and intervertebral instability to LF hypertrophy and buckling were assessed. <h3>Results</h3> Measurements were performed from C2-3 to C7-T1 in 169 patients who satisfied the eligibility criteria, making a total of 1014 levels. The samples were divided into 2 groups: 798 levels with buckling &lt;1 mm (group A) and 216 levels with buckling &gt;1 mm (group B). Of those, 161 levels satisfied the criteria for radiological instability (sagittal translation/rotation). No correlation was observed between age/disc height and buckling. Intervertebral instability showed significant association (<i>P</i> = 0.046) with buckling. No correlation was found between age/intervertebral instability and hypertrophy. <h3>Conclusion</h3> LF buckling but not hypertrophy is related to intervertebral instability in the cervical spine. LF buckling in the cervical spine is not related to age or disc height in the cervical spine. <h3>Clinical Relevance</h3> Intervertebral instability on dynamic x-ray imaging of the cervical spine can be a predictor of ligamentum flavum buckling and can be utilized for surgical planning. <h3>Level of Evidence</h3> 3.
Covid-19: Antiviral purchased by UK government does not lower risk of hospital admission, trial shows
Authors: Jacqui Wise
Journal: BMJ (2022)

Covid-19: Antiviral purchased by UK government does not lower risk of hospital admission, trial shows Jacqui WiseMolnupiravir, a covid-19 antiviral drug bought by the UK government in the amount of 2.23 million doses, is no better than placebo at lowering the risks of death and hospital admission, a pivotal UK trial has found.
Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1
Authors: Jiming Chen, Jie Yang, Wenhui Wang, Danfeng Guo, Chengyan Zhang, Shibo Wang, Xinliang Lu, Xiaofang Huang, Pingli Wang, Gensheng Zhang, Jing Zhang, Jianli Wang, Zhijian Cai
Journal: Cellular and Molecular Immunology (2022)

Abstract PD-L1 + tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1 + TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1 + TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1 + Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.
A triple-RBD-based mucosal vaccine provides broad protection against SARS-CoV-2 variants of concern
Authors: Jingyi Yang, Mei-Qin Liu, Lin Liu, Xian Li, Mengxin Xu, Haofeng Lin, Shuning Liu, Yunqi Hu, Bei Li, Bowen Liu, Min Li, Ying Sun, Yao-Qing Chen, Zheng-Li Shi, Huimin Yan
Journal: Cellular and Molecular Immunology (2022)
Atrial fibrillation: Most UK media “promote screening” despite lack of evidence, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2022)

The long-term effectiveness of zonisamide (ZNS) was evaluated in 11 patients with West syndrome (7 symptomatic) who had cessation of spasms with ZNS monotherapy. During the follow-up period (24 to 79 months, mean = 53 months), this response was maintained in 7 patients (3 symptomatic, relapse rate = 36%), including 2 children in whom ZNS was successfully discontinued. No serious adverse reactions were noted. ZNS may be both effective and well tolerated for the treatment of West syndrome.
EspH interacts with the host active Bcr related (ABR) protein to suppress RhoGTPases
Authors: Rachana Pattani Ramachandran, Ipsita Nandi, Nir Haritan, Efrat Zlotkin-Rivkin, Yael Keren, Tsafi Danieli, Mario Lebendiker, Naomi Melamed-Book, William Breuer, Dana Reichmann, Benjamin Aroeti
Journal: Gut Microbes (2022)

Enteropathogenic Escherichia coli are bacterial pathogens that colonize the gut and cause severe diarrhea in humans. Upon intimate attachment to the intestinal epithelium, these pathogens translocate via a type III secretion system virulent proteins, termed effectors, into the host cells. These effectors manipulate diverse host cell organelles and functions for the pathogen's benefit. However, the precise mechanisms underlying their activities are not fully understood despite intensive research. EspH, a critical effector protein, has been previously reported to disrupt the host cell actin cytoskeleton by suppressing RhoGTPase guanine exchange factors. However, native host proteins targeted by EspH to mediate these activities remained unknown. Here, we identified the active Bcr related (ABR), a protein previously characterized to possess dual Rho guanine nucleotide exchange factor and GTPase activating protein (GAP) domains, as a native EspH interacting partner. These interactions are mediated by the effector protein's C-terminal 38 amino acid segment. The effector primarily targets the GAP domain of ABR to suppress Rac1 and Cdc42, host cell cytotoxicity, bacterial invasion, and filopodium formation at infection sites. Knockdown of ABR expression abolished the ability of EspH to suppress Rac1, Cdc42. Our studies unravel a novel mechanism by which host RhoGTPases are hijacked by bacterial effectors.
Nurse-to-Nurse Familiarity and Mortality in the Critically Ill: A Multicenter Observational Study
Authors: Antoine Duclos, Cécile Payet, Loredana Baboi, Bernard Allaouchiche, Laurent Argaud, Frédéric Aubrun, Julien Bohé, Frédéric Dailler, Jean-Luc Fellahi, Jean-Jacques Lehot, Vincent Piriou, Thomas Rimmelé, Delphine Terragrossa, Stéphanie Polazzi, Claude Guérin
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Nurse-to-nurse familiarity at work should strengthen the components of teamwork and enhance its efficiency. However, its impact on patient outcomes in critical care remains poorly investigated. Objectives: To explore the role of nurse-to-nurse familiarity on inpatient deaths during ICU stay. Methods: This was a retrospective observational study in eight adult academic ICUs between January 1, 2011 and December 31, 2016. Measurements and Main Results: Nurse-to-nurse familiarity was measured across day and night 12-hour daily shifts as the mean number of previous collaborations between each nursing team member during previous shifts within the given ICU (suboptimal if <50). Primary outcome was a shift with at least one inpatient death, excluding death of patients with a decision to forego life-sustaining therapy. A multiple modified Poisson regression was computed to identify the determinants of mortality per shift, taking into account ICU, patient characteristics, patient-to-nurse and patient-to-assistant nurse ratios, nurse experience length, and workload. A total of 43,479 patients were admitted, of whom 3,311 (8%) died. The adjusted model showed a lower risk of a shift with mortality when nurse-to-nurse familiarity increased in the shift (relative risk, 0.90; 95% confidence interval per 10 shifts, 0.82-0.98; P = 0.012). Low nurse-to-nurse familiarity during the shift combined with suboptimal patient-to-nurse and patient-to-assistant nurse ratios (suboptimal if >2.5 and >4, respectively) were associated with increased risk of shift with mortality (relative risk, 1.84; 95% confidence interval, 1.15-2.96; P < 0.001). Conclusions: Shifts with low nurse-to-nurse familiarity were associated with an increased risk of patient deaths.
SMAD4 Loss Induces c-MYC–Mediated NLE1 Upregulation to Support Protein Biosynthesis, Colorectal Cancer Growth, and Metastasis
Authors: Leon P. Loevenich, Markus Tschurtschenthaler, Matjaz Rokavec, Miguel G. Silva, Moritz Jesinghaus, Thomas Kirchner, Frederick Klauschen, Dieter Saur, Jens Neumann, Heiko Hermeking, Peter Jung
Journal: Cancer Research (2022)

Abstract Growth and metastasis of colorectal cancer is closely connected to the biosynthetic capacity of tumor cells, and colorectal cancer stem cells that reside at the top of the intratumoral hierarchy are especially dependent on this feature. By performing disease modeling on patient-derived tumor organoids, we found that elevated expression of the ribosome biogenesis factor NLE1 occurs upon SMAD4 loss in TGFβ1-exposed colorectal cancer organoids. TGFβ signaling-mediated downregulation of NLE1 was prevented by ectopic expression of c-MYC, which occupied an E-box–containing region within the NLE1 promoter. Elevated levels of NLE1 were found in colorectal cancer cohorts compared with normal tissues and in colorectal cancer subtypes characterized by Wnt/MYC and intestinal stem cell gene expression. In colorectal cancer cells and organoids, NLE1 was limiting for de novo protein biosynthesis. Upon NLE1 ablation, colorectal cancer cell lines activated p38/MAPK signaling, accumulated p62- and LC3-positive structures indicative of impaired autophagy, and displayed more reactive oxygen species. Phenotypically, knockout of NLE1 inhibit.ed proliferation, migration and invasion, clonogenicity, and anchorage-independent growth. NLE1 loss also increased the fraction of apoptotic tumor cells, and deletion of TP53 further sensitized NLE1-deficient colorectal cancer cells to apoptosis. In an endoscopy-guided orthotopic mouse transplantation model, ablation of NLE1 impaired tumor growth in the colon and reduced primary tumor-derived liver metastasis. In patients with colorectal cancer, NLE1 mRNA levels predicted overall and relapse-free survival. Taken together, these data reveal a critical role of NLE1 in colorectal cancer growth and progression and suggest that NLE1 represents a potential therapeutic target in colorectal cancer patients. Significance: NLE1 limits de novo protein biosynthesis and the tumorigenic potential of advanced colorectal cancer cells, suggesting NLE1 could be targeted to improve the treatment of metastatic colorectal cancer.
Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
Authors: Anna Borgenvik, Karl O. Holmberg, Sara Bolin, Miao Zhao, Vasil Savov, Gabriela Rosén, Sonja Hutter, Alexandra Garancher, Aldwin Suryo Rahmanto, Tobias Bergström, Thale Kristin Olsen, Oliver J. Mainwaring, Damiana Sattanino, Annemieke D. Verbaan, Jessica M. Rusert, Anders Sundström, Mar Ballester Bravo, Yonglong Dang, Amelie S. Wenz, Stacey Richardson, Grammatiki Fotaki, Rebecca M. Hill, Adrian M. Dubuc, Antonia Kalushkova, Marc Remke, Matko Čančer, Helena Jernberg-Wiklund, Géraldine Giraud, Xingqi Chen, Michael D. Taylor, Olle Sangfelt, Steven C. Clifford, Ulrich Schüller, Robert J. Wechsler-Reya, Holger Weishaupt, Fredrik J. Swartling
Journal: Cancer Research (2022)

Abstract Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial–mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation
Authors: Jessica C. Lal, Chengsheng Mao, Yadi Zhou, Shamone R. Gore-Panter, Julie H. Rennison, Beth S. Lovano, Laurie Castel, Jiyoung Shin, A. Marc Gillinov, Jonathan D. Smith, John Barnard, David R. Van Wagoner, Yuan Luo, Feixiong Cheng, Mina K. Chung
Journal: Cell Reports Medicine (2022)

Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36–0.64, p < 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug.
Sylvia Joyce Jordan
Authors: Jennifer Trigg, Hilary Trigg, Cecilia Trigg, Miles Trigg
Journal: BMJ (2022)

<h3>BACKGROUND:</h3> Tobacco smoke has detrimental effects on the respiratory system. This study investigated the associations of active and passive smoking with asthma symptoms in Hong Kong adolescents. <h3>METHODS:</h3> A total of 6,494 Hong Kong secondary school students, with a mean ± SD age of 15.0 ± 1.21 years, participated in the Health Related Behavior General Survey in 2000–2001. They reported their demographic factors (sex, age, housing type, district of living), lifestyles (smoking, drinking, extracurricular sports, eating), and asthma symptoms (exercise-induced bronchospasm [EIB] and nocturnal cough) in the questionnaire. In addition, number of smoking parents (none/one/both) and presence of a smoking best friend (yes/no) were assessed. Logistic regression models were used to determine the odds ratios (OR) of frequently having the asthma symptoms for different smoking status of students, parents, and best friend, with adjustment for demographic factors and lifestyles. <h3>RESULTS:</h3> The prevalence of former, light, and heavy smokers was 17.5%, 7.7%, and 1.0%, respectively. Moreover, 35.1% of the participants had one and 3.8% had 2 parents who smoked. Heavy smokers were more likely to experience EIB with OR (95% CI) of 2.27 (1.30–3.97) and nocturnal cough with OR (95% CI) of 3.45 (1.52–7.81), as well as both symptoms with OR (95% CI) = 4.69 (1.88–11.73) when compared to those who never smoked. The corresponding OR (95% CI) for having at least one smoking parent and a smoking best friend was 1.45 (1.17–1.81), 1.61 (1.06–2.42), and 2.43 (1.37–4.31), when compared with those without a parent or best friend who smoked. <h3>CONCLUSIONS:</h3> Adolescents who are heavy smokers and having parents and a best friend who smoke are more likely than others to have asthma symptoms. Both active and passive smoking are related to asthma symptoms in adolescents.
Kenneth Theodore Evans
Authors: S Haslam, V Stephens, P Curtis, G Haworth, J Haslam
Journal: BMJ (2022)

<h3>Abstract</h3> N95 filtering facepiece respirators (FFRs) are essential for the protection of healthcare professionals and other high-risk groups against Coronavirus Disease of 2019 (COVID-19). In response to shortages in FFRs during the ongoing COVID-19 pandemic, the Food and Drug Administration issued an Emergency Use Authorization permitting FFR decontamination and reuse. However, although industrial decontamination services are available at some large institutions, FFR decontamination is not widely accessible. To be effective, FFR decontamination must 1) inactivate the virus; 2) preserve FFR integrity, specifically fit and filtering capability; and 3) be non-toxic and safe. Here we identify and test at-home heat-based methods for FFR decontamination that meet these requirements using common household appliances. Our results identify potential protocols for simple and accessible FFR decontamination, while also highlighting unsuitable methods that may jeopardize FFR integrity. <h3>One sentence summary</h3> Survey of at-home methods for N95 respirator decontamination using heat and evaluation of their effects on N95 respirator integrity.
Association of Sodium-Glucose Cotransporter-2 Inhibitors With Incident Atrial Fibrillation in Older Adults With Type 2 Diabetes
Authors: Min Zhuo, Elvira D’Andrea, Julie M. Paik, Deborah J. Wexler, Brendan M. Everett, Robert J. Glynn, Seoyoung C. Kim, Elisabetta Patorno
Journal: JAMA Network Open (2022)

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point.
SARS CoV-2 Seroprevalence in Selected States of High and Low Disease Burden in Nigeria
Authors: Olatunji Matthew Kolawole, Oyewale Tomori, Dennis Agbonlahor, Ekanem Ekanem, Rasheed Bakare, Nasidi Abdulsalam, Obehi Okojie, Eka Braide, Benjamin Uzochukwu, Abdulmumini Rafindadi, Shaibu Bello, Sule Shehu, Oye Gureje, Muhammed Lecky, Obinna Onwujekwe, Cajetan Onyedum, Adaobi Ezike, David Bukbuk, Garba Ashir, Bond Anyaehie, Uche Amazigo, Abdulrajak Habib, Joy Ufere, Ngozi Azodoh
Journal: JAMA Network Open (2022)

Importance The global impact of COVID-19 has led to an increased need to continuously assess disease surveillance tools. The utility of SARS-CoV-2 serologic tools in determining immunity levels across different age groups and locations in helping to quickly assess the burden of COVID-19 with significant health policy implications is unknown. Objective To determine the prevalence of SARS-CoV-2 antibodies with respect to the age group and sex of participants. Design, Setting, and Participants A cross-sectional survey of 4904 individuals across 12 states with high and low COVID-19 disease burden in Nigeria was carried out between June 29 and August 21, 2021. Main Outcomes and Measures Enzyme-linked immunosorbent assay was used for the detection of specific SARS-CoV-2 immunoglobulin G and immunoglobulin M antibodies, such as the nucleocapsid protein-NCP and spike protein S1. Interviewer-administered questionnaires provided information on participants’ history of disease and associated risk factors. Results A total of 4904 individuals participated in the study (3033 were female [61.8%]; mean [SD] age, 26.7 [6.51] years). A high seroprevalence of SARS-CoV-2 (78.9%) was obtained. Seropositivity was consistent across the states surveyed, ranging from 69.8% in Lagos to 87.7% in Borno. There was no association between sex and seropositivity (female, 2414 [79.6%]; male, 1456 [77.8%]; P = .61); however, an association was noted between age and seropositivity, with the peak prevalence observed in participants aged 15 to 19 years (616 [83.6%]; P = .001). Similarly, loss of appetite (751 [82.3%]; P = .04) and smell (309 [84.4%]; P = .01) were associated with seropositivity. Conclusions and Relevance In this cross-sectional study, a high SARS-CoV-2 seroprevalence was obtained among the study population during the low level of vaccination at the time of the survey. Thus, there is a need for both an efficacy and antibody neutralization test study to ascertain the efficacy of the antibody detected and the potential for herd immunity in Nigeria.